Prognostic impact of genetic abnormalities in 536 first-line chronic lymphocytic leukaemia patients without 17p deletion treated with chemoimmunotherapy in two prospective trials: Focus on IGHV-mutated subgroups (a FILO study).

The potential prognostic influence of genetic aberrations on chronic lymphocytic leukaemia (CLL) can vary based on various factors, such as the immunoglobulin heavy variable (IGHV) status. We conducted an integrative analysis on genetic abnormalities identified through cytogenetics and targeted next-generation sequencing in 536 CLL patients receiving first-line chemo(immuno)therapies (CIT) as part of two prospective trials. We evaluated the prognostic implications of the main abnormalities, with specific attention to their relative impact according to IGHV status. In the entire cohort, unmutated (UM)-IGHV, complex karyotype, del(11q) and ATM mutations correlated significantly with shorter progression-free survival (PFS). Focusing on the subset of mutated IGHV (M-IGHV) patients, univariate analysis showed that complex karyotype, del(11q), SF3B1 and SAMHD1 mutations were associated with significant lower PFS. The prognostic influence varied based on the patient's IGHV status, as these abnormalities did not affect outcomes in the UM-IGHV subgroup. TP53 mutations had no significant impact on outcomes in the M-IGHV subgroup. Our findings highlight the diverse prognostic influence of genetic aberrations depending on the IGHV status in symptomatic CLL patients receiving first-line CIT. The prognosis of gene mutations and cytogenetic abnormalities needs to be investigated with a compartmentalized methodology, taking into account the IGVH status of patients receiving first-line BTK and/or BCL2 inhibitors.

Exploring the dynamics of astaxanthin production in Haematococcus pluvialis biofilms using a rotating biofilm-based system.

Microalgae biofilm emerged as a solid alternative to conventional suspended cultures which present high operative costs and complex harvesting processes. Among several designs, rotating biofilm-based systems stand out for their scalability, although their primary applications have been in wastewater treatment and aquaculture. In this work, a rotating system was utilized to produce a high-value compound (astaxanthin) using Haematococcus pluvialis biofilms. The effect of nitrogen regime, light intensity, and light history on biofilm traits was assessed to better understand how to efficiently operate the system. Our results show that H. pluvialis biofilms follow the classical growth stages described for bacterial biofilms (from adhesion to maturation) and that a two-stage (green and red stages) allowed to reach astaxanthin productivities of 204 mg m-2 d-1 . The higher light intensity applied during the red stage (400 and 800 µmol m-2 s-1 ) combined with nitrogen depletion stimulated similar astaxanthin productivities. However, by training the biofilms during the green stage, using mild-light intensity (200 µmol m-2 s-1 ), a process known as priming, the final astaxanthin productivity was enhanced by 40% with respect to biofilms pre-exposed to 50 µmol m-2 s-1 . Overall, this study shows the possibility of utilizing rotating microalgae biofilms to produce high-value compounds laying the foundation for further biotechnological applications of these emerging systems.

Comment on "Binding Debye-Hückel theory for associative electrolyte solutions" [J. Chem. Phys. 159, 154503 (2023)].

It is argued that the Binding Debye-Hückel (BiDH) model proposed by Naseri Boroujeni et al. [J. Chem. Phys. 159, 154503 (2023)] might not be appropriate for the description of Monte Carlo simulation data obtained for primitive model electrolytes. The first reason is that the original Debye-Hückel (DH) theory is of low accuracy for describing deviations from ideality in concentrated solutions of strong salts. The DH framework is thus a poor basis for building a model including association. The second reason is that the mean-spherical approximation, without assumption of association, apparently predicts Monte Carlo (MC) data for primitive electrolytes better than BiDH. Thus, the BiDH model seems to be simply a way of compensating for the deficiencies of DH theory by assuming association.

Long-term outcomes of patients with type 1 or 2 autoimmune hepatitis presenting in childhood.

BACKGROUND & AIMS: In children with autoimmune hepatitis, uncertainties include outcomes associated with type 2 hepatitis, the possibility of and criteria for attempting withdrawal of treatment, and long-term outcomes. We report our experience on these issues. METHODS: From 1973 to 2002, 117 children with type 1 (n = 65) or type 2 (n = 52) hepatitis, excluding fulminant hepatitis, were treated, primarily with prednisone and azathioprine. Median follow-up was 20 years in survivors. RESULTS: Normalisation of aminotransferases and prothrombin ratio were observed in 93% and 84% of children, respectively; sustained remission after treatment withdrawal was recorded in 24% of the entire population, with a median follow-up of 7 years. Sustained treatment-free remission was obtained in 11 of 24 children with follow-ups of 4-22 years based on durable normalisation of aminotransferases (without histological assessment). Gastrointestinal bleeding from varices and the emergence of extrahepatic autoimmune disorders occurred in 10 and 22 patients, respectively. Liver transplantation was performed in 23 patients at a median age of 21 years. The 30-year probabilities of overall and native liver survival were 81% and 61%, respectively. No differences were observed between type 1 and 2 hepatitis for any of the component parts of outcome. In the multivariate analysis, a persistent abnormal prothrombin ratio was associated with worse probabilities of overall and native liver survival. CONCLUSIONS: In terms of liver outcome, type 2 hepatitis is not different from type 1. Withdrawal of treatment is possible without prior liver histology. A persistent abnormal prothrombin ratio identifies patients who will require liver transplantation in adolescence or early adulthood. IMPACT AND IMPLICATIONS: In children with autoimmune hepatitis, there are conflicting reports on the differences in outcome between type 1 and type 2 hepatitis, and on the possibility of treatment withdrawal, before which liver histology is required; data concerning >10-year overall and native liver survival rates are limited. In this study, we found no differences in outcomes between type 1 and 2 hepatitis; a durable treatment-free state was achieved in 19% of all patients throughout childhood and early adulthood, and in 45% of children for whom treatment withdrawal was attempted without prior liver histology; prothrombin was found to be predictive of 30-year overall and native liver survival. The results allow for a less-strict approach to treatment withdrawal in children, avoiding the risks of a liver biopsy, and they provide a tool to help anticipate the need for liver transplantation before complications occur.

High frequency of clonal hematopoiesis in Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a clonal hematopoietic disorder characterized by the accumulation of foamy histiocytes within organs (in particular, frequent retroperitoneal involvement) and a high frequency of BRAFV600E mutations. Although ECD is not commonly recognized to have overt peripheral blood (PB) or bone marrow (BM) disease, we recently identified that ECD patients have a high frequency of a concomitant myeloid malignancy. We thus conducted a systematic clinical and molecular analysis of the BM from 120 ECD patients. Surprisingly, 42.5% of ECD patients (51 of 120) had clonal hematopoiesis whereas 15.8% of patients (19 of 120) developed an overt hematologic malignancy (nearly all of which were a myeloid neoplasm). The most frequently mutated genes in BM were TET2, ASXL1, DNMT3A, and NRAS. ECD patients with clonal hematopoiesis were more likely to be older (P < .0001), have retroperitoneal involvement (P = .02), and harbor a BRAFV600E mutation (P = .049) than those without clonal hematopoiesis. The presence of the TET2 mutation was associated with a BRAFV600E mutation in tissue ECD lesions (P = .0006) and TET2-mutant ECD patients were more likely to have vascular involvement than TET2 wild-type ECD patients. Clonal hematopoiesis mutations in ECD were detected in cells derived from CD34+CD38- BM progenitors and PB monocytes but less frequently present in PB B and T lymphocytes. These data identify a heretofore unrecognized high frequency of clonal hematopoiesis in ECD patients, reaffirm the development of additional high risk of myeloid neoplasms in ECD, and provide evidence of a BM-based precursor cell of origin for many patients with ECD.

High-efficiency non-ablative UV laser nano-scale processing of fused silica by stable filamentation.

Over the last decades, three-dimensional micro-manufacturing of fused silica via near-infrared ultrafast laser exposure combined with an etching step has become an established technique for producing complex three-dimensional components. Here, we explore the effect of ultraviolet exposure on process efficiency. Specifically, we demonstrate that shorter wavelengths not only enable enhanced resolution but also yield higher etching selectivity, with an order of magnitude lower pulse energy and significantly higher repetition rates than current practice. This result is obtained using an exposure regime where the laser beam alternates between regimes of self-focusing and defocusing in a stable manner, forming a localized filament. Using this principle, we demonstrate the fabrication of self-organized nano-channels with diameters as small as 120 nm after etching, reaching extreme aspect ratios, exceeding 1500.

Understanding photosynthetic biofilm productivity and structure through 2D simulation.

We present a spatial model describing the growth of a photosynthetic microalgae biofilm. In this 2D-model we consider photosynthesis, cell carbon accumulation, extracellular matrix excretion, and mortality. The rate of each of these mechanisms is given by kinetic laws regulated by light, nitrate, oxygen and inorganic carbon. The model is based on mixture theory and the behaviour of each component is defined on one hand by mass conservation, which takes into account biological features of the system, and on the other hand by conservation of momentum, which expresses the physical properties of the components. The model simulates the biofilm structural dynamics following an initial colonization phase. It shows that a 75 µm thick active region drives the biofilm development. We then determine the optimal harvesting period and biofilm height which maximize productivity. Finally, different harvesting patterns are tested and their effect on biofilm structure are discussed. The optimal strategy differs whether the objective is to recover the total biofilm or just the algal biomass.

Sequence analyses of relapsed or refractory diffuse large B-cell lymphomas unravel three genetic subgroups of patients and the GNA13 mutant as poor prognostic biomarker, results of LNH-EP1 study.

Advances in molecular profiling of newly diagnosed diffuse large B-cell lymphoma (DLBCL) have recently refine genetic subgroups. Genetic subgroups remain undetermined at the time of relapse or refractory (RR) disease. This study aims to decipher genetic subgroups and search for prognostic molecular biomarkers in patients with RR-DLBCL. From 2015 to 2021, targeted next-generation sequencing analyses of germline-matched tumor samples and fresh tissue from RR-DLBCL patients were performed. Unsupervised clustering of somatic mutations was performed and correlations with patient outcome were sought. A number of 120 patients with RR-DLBCL were included in LNH-EP1 study and a molecular tumor landscape was successfully analyzed in 87% of patients (104/120 tumor samples). The median age was 67.5 years (range 27.4-87.4), median number of previous treatments was 2 (range 1-9). The most frequently mutated genes were TP53 (n = 53 mutations; 42% of samples), CREBBP (n = 39; 32%), BCL2 (n = 86; 31%), KMT2D (n = 39; 28%) and PIM1 (n = 54; 22%). Unsupervised clustering separated three genetic subgroups entitled BST (enriched in BCL2, SOCS1, and TNFRSF14 mutations); TKS (enriched in TP53, KMT2D, and STAT6 mutations); and PCM (enriched in PIM1, CD79B, and MYD88 mutations). Median overall survival (OS) was 11.0 (95% confidence interval [CI]: 8.1-12.6) months. OS was not significantly different between the three genetic subgroups. GNA13 mutant was significantly associated with an increased risk of death (hazard ratio: 6.6 [95% CI: 2.1-20.6]; p = .0011) and shorter OS (p = .0340). At the time of relapse or refractory disease, three genetic subgroups of DLBCL patients were delineated, which could help advance precision molecular medicine programs.

Relationship between large and small for gestational age and hospital readmission after postpartum discharge: a population-based, data-linkage study.

This study aims to determine the association of small for gestational age (SGA) and large for gestational age (LGA) at birth with hospital readmission after postpartum discharge for up to 28 days of delivery. This is a population-based, data-linkage study using the French National Uniform Hospital Discharge Database. "Healthy" singleton term infants born between January 1st, 2017, and November 30th, 2018, in the French South region were included. SGA and LGA were defined as birth weight < 10th and > 90th percentiles, respectively, according to sex and gestational age. A multivariable regression analysis was performed. Among 67,359 included infants, 2441 (3.6%) were readmitted, and 61% of them were hospitalized within 14 days postpartum. Hospitalized infants were more likely to be LGA at birth (10.3% vs. 8.6% in non-hospitalized infants, p < 0.01); the proportion of SGA infants did not differ between both groups. Compared to appropriate birth weight for GA (AGA) infants, LGA infants were more often hospitalized for infectious diseases (57.7% vs. 51.3%, p = 0.05). After regression analysis, LGA infants had a 20% higher odds of being hospitalized than those born AGA (aOR (95%CI) = 1.21 (1.06-1.39)), while aOR (95%CI) for SGA was 1.11 (0.96-1.28). CONCLUSION:  In contrast to SGA, LGA was associated with hospital readmission during the first month of life. Follow-up protocols that include LGA should be evaluated. WHAT IS KNOWN: • Newborns are at high risk of hospital readmission during the postpartum period. • However, the influence of appropriateness for gestational age at birth, i.e. being born small for gestational age (SGA) or large for gestational age (LGA), has been little evaluated. WHAT IS NEW: • In contrast to SGA born infants, we found that infants born LGA were at high risk of hospital admission and the main cause was infectious diseases. • This population should be considered at risk of early adverse outcomes and should require attentive medical follow-up after postpartum discharge.

On analytical theories for conductivity and self-diffusion in concentrated electrolytes.

Describing analytically the transport properties of electrolytes, such as their conductivity or the self-diffusion of the ions, has been a central challenge of chemical physics for almost a century. In recent years, this question has regained some interest in light of Stochastic Density Field Theory (SDFT) - an analytical framework that allows the approximate determination of density correlations in fluctuating systems. In spite of the success of this theory to describe dilute electrolytes, its extension to concentrated solutions raises a number of technical difficulties, and requires simplified descriptions of the short-range repulsion between the ions. In this article, we discuss recent approximations that were proposed to compute the conductivity of electrolytes, in particular truncations of Coulomb interactions at short distances. We extend them to another observable (the self-diffusion coefficient of the ions) and compare them to earlier analytical approaches, such as the mean spherical approximation and mode-coupling theory. We show how the treatment of hydrodynamic effects in SDFT can be improved, that the choice of the modified Coulomb interactions significantly affects the determination of the properties of the electrolytes, and that comparison with other theories provides a guide to extend SDFT approaches in this context.

Theoretical growth rate of microalgae under high/low-flashing light.

Dynamic light regimes strongly impact microalgal photosynthesis efficiency. Finding the optimal way to supply light is then a tricky problem, especially when the growth rate is inhibited by overexposition to light and, at the same time, there is a lack of light in the deepest part of the culture. In this paper, we use the Han model to study the theoretical microalgal growth rate by applying periodically two different light intensities. Two approaches are considered depending on the period of the light pattern. For a large light period, we demonstrate that the average photosynthetic rate can be improved under some conditions. Moreover, we can also enhance the growth rate at steady state as given by the PI-curve. Although, these conditions change through the depth of a bioreactor. This theoretical improvement in the range of 10-15% is due to a recovery of photoinhibited cells during the high irradiance phase. We give a minimal value of the duty cycle for which the optimal irradiance is perceived by the algae culture under flashing light regime.

Quality Indexes of the ECG Signal Transmitted Using Optical Wireless Link.

This work relates to the quality of the electrocardiogram (ECG) signal of an elderly person, transmitted using optical wireless links. The studied system uses infrared signals between an optical transmitter located on the person's wrist and optical receivers placed on the ceiling. As the elderly person moves inside a room, the optical channel is time-varying, affecting the received ECG signal. To assess the ECG quality, we use specific signal quality indexes (SQIs), allowing the evaluation of the spectral and statistical characteristics of the signal. Our main contribution is studying how the SQIs behave according to the optical transmission performance and the studied context in order to determine the conditions required to obtain excellent quality indexes. The approach is based on the simulation of the whole chain, from the raw ECG to the extraction process after transmission until the evaluation of SQIs. This technique was developed considering optical channel modeling, including the mobility of the elderly. The obtained results show the potential of optical wireless communication technologies for reliable ECG monitoring in such a context. It has been observed that excellent ECG quality can be obtained with a minimum SNR of 11 dB for on-off keying modulation.

Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis.

DNA methylation is tightly regulated throughout mammalian development, and altered DNA methylation patterns are a general hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in hematological disorders, including acute myeloid leukemia (AML), and has been suggested to protect CG dinucleotide (CpG) islands and promoters from aberrant DNA methylation. In this study, we present a novel Tet2-dependent leukemia mouse model that closely recapitulates gene expression profiles and hallmarks of human AML1-ETO-induced AML. Using this model, we show that the primary effect of Tet2 loss in preleukemic hematopoietic cells is progressive and widespread DNA hypermethylation affecting up to 25% of active enhancer elements. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner but increases relative to population doublings. We confirmed this specific enhancer hypermethylation phenotype in human AML patients with TET2 mutations. Analysis of immediate gene expression changes reveals rapid deregulation of a large number of genes implicated in tumorigenesis, including many down-regulated tumor suppressor genes. Hence, we propose that TET2 prevents leukemic transformation by protecting enhancers from aberrant DNA methylation and that it is the combined silencing of several tumor suppressor genes in TET2 mutated hematopoietic cells that contributes to increased stem cell proliferation and leukemogenesis.

Identification of 2 DNA methylation subtypes of Waldenström macroglobulinemia with plasma and memory B-cell features.

Epigenetic changes during B-cell differentiation generate distinct DNA methylation signatures specific for B-cell subsets, including memory B cells (MBCs) and plasma cells (PCs). Waldenström macroglobulinemia (WM) is a B-cell malignancy uniquely comprising a mixture of lymphocytic and plasmacytic phenotypes. Here, we integrated genome-wide DNA methylation, transcriptome, mutation, and phenotypic features of tumor cells from 35 MYD88-mutated WM patients in relation to normal plasma and B-cell subsets. Patients naturally segregate into 2 groups according to DNA methylation patterns, related to normal MBC and PC profiles, and reminiscent of other memory and PC-derived malignancies. Concurrent analysis of DNA methylation changes in normal and WM development captured tumor-specific events, highlighting a selective reprogramming of enhancer regions in MBC-like WM and repressed and heterochromatic regions in PC-like WM. MBC-like WM hypomethylation was enriched in motifs belonging to PU.1, TCF3, and OCT2 transcription factors and involved elevated MYD88/TLR pathway activity. PC-like WM displayed marked global hypomethylation and selective overexpression of histone genes. Finally, WM subtypes exhibited differential genetic, phenotypic, and clinical features. MBC-like WM harbored significantly more clonal CXCR4 mutations (P = .015), deletion 13q (P = .006), splenomegaly (P = .02), and thrombocytopenia (P = .004), whereas PC-like WM harbored more deletion 6q (P = .012), gain 6p (P = .033), had increased frequencies of IGHV3 genes (P = .002), CD38 expression (P = 4.1e-5), and plasmacytic differentiation features (P = .008). Together, our findings illustrate a novel approach to subclassify WM patients using DNA methylation and reveal divergent molecular signatures among WM patients.

Human erythroleukemia genetics and transcriptomes identify master transcription factors as functional disease drivers.

Acute erythroleukemia (AEL or acute myeloid leukemia [AML]-M6) is a rare but aggressive hematologic malignancy. Previous studies showed that AEL leukemic cells often carry complex karyotypes and mutations in known AML-associated oncogenes. To better define the underlying molecular mechanisms driving the erythroid phenotype, we studied a series of 33 AEL samples representing 3 genetic AEL subgroups including TP53-mutated, epigenetic regulator-mutated (eg, DNMT3A, TET2, or IDH2), and undefined cases with low mutational burden. We established an erythroid vs myeloid transcriptome-based space in which, independently of the molecular subgroup, the majority of the AEL samples exhibited a unique mapping different from both non-M6 AML and myelodysplastic syndrome samples. Notably, >25% of AEL patients, including in the genetically undefined subgroup, showed aberrant expression of key transcriptional regulators, including SKI, ERG, and ETO2. Ectopic expression of these factors in murine erythroid progenitors blocked in vitro erythroid differentiation and led to immortalization associated with decreased chromatin accessibility at GATA1-binding sites and functional interference with GATA1 activity. In vivo models showed development of lethal erythroid, mixed erythroid/myeloid, or other malignancies depending on the cell population in which AEL-associated alterations were expressed. Collectively, our data indicate that AEL is a molecularly heterogeneous disease with an erythroid identity that results in part from the aberrant activity of key erythroid transcription factors in hematopoietic stem or progenitor cells.

The architecture and metabolic traits of monospecific photosynthetic biofilms studied in a custom flow-through system.

Microalgae biofilms have great ecological importance and high biotechnological potential. Nevertheless, an in-depth and combined structural (i.e., the architecture of the biofilm) and physiological characterization of microalgae biofilms is still missing. An approach able to provide the same time physiological and structural information during biofilm growth would be of paramount importance to understand these complex biological systems and to optimize their productivity. In this study, monospecific biofilms of a diatom and a green alga were grown under dynamic conditions in custom flow cells represented by UV/Vis spectroscopic cuvettes. Such flow cells were conceived to characterize the biofilms by several techniques mostly in situ and in a nondestructive way. Physiological traits were obtained by measuring variable chlorophyll a fluorescence by pulse amplitude modulated fluorometry and by scanning the biofilms in a spectrometer to obtain in vivo pigments spectral signatures. The architectural features were obtained by imaging the biofilms with a confocal laser scanning microscopy and an optical coherence tomography. Overall, this experimental setup allowed us to follow the growth of two biofilm-forming microalgae showing that cell physiology is more affected in complex biofilms likely as a consequence of alterations in local environmental conditions.

A Model for Early Endoscopic Detection of High-Risk Gastroesophageal Varices in Children With Biliary Atresia.

OBJECTIVE: In children with biliary atresia and portal hypertension, progression to gastroesophageal varices carrying a risk of bleeding depends on age, total serum bilirubin concentration and initial endoscopic features. We report an attempt to use these factors for early detection of high-risk varices (HRVs). METHODS: Based on different combinations of these factors, a model was set to estimate the probabilities of emergence of HRVs at various time intervals. A 10% probability was chosen to set the date of the next endoscopy in children who did not display HRVs initially. A total of 113 children without HRVs who underwent their first endoscopy before age 8 in 2013-2020 were included. A comparison was made with children seen during the period 1990-2012 when this model was not used. RESULTS: In all, 65 of the 113 children underwent one to five additional endoscopies at dates set according to the model. The emergence of HRVs was recorded in 22 children after a mean interval of 14 months and was managed by endoscopic primary prophylaxis in all but one who underwent liver transplantation. Three other children bled before the next planned endoscopy. Compared with 175 children of the same age ranges without HRVs in the period 1990-2012, the use of the model was associated with a faster detection of HRVs with a lower number of endoscopic procedures (P  = 0.0022 and P  = 0.023, respectively). CONCLUSION: The results suggest that the model reported may be a useful tool for the early detection of HRVs to allow primary prophylaxis of bleeding.

Efficacy and Safety of Endoscopic Primary Prophylaxis of Bleeding in Children With High-Risk Gastroesophageal Varices.

OBJECTIVES: Primary prophylaxis of bleeding is debated in children with gastroesophageal varices; one of the reasons is the limited number of studies concerning its efficacy and safety. We report our experience with endoscopic primary prophylaxis. METHODS: From 2006 to 2019, 145 children (median age, 3.5 years; cirrhosis, n = 116) with high-risk gastroesophageal varices underwent primary prophylaxis (banding, n = 114; sclerotherapy n = 31, primarily in smaller children). RESULTS: We observed the eradication of varices in 93% of children after a mean of 6 months, at least one recurrence of varices in 45% after eradication, and gastrointestinal bleeding in 17% of children. Irrespective of the cause of portal hypertension, grade 3 esophageal varices, presence of gastric varices along the cardia and a lower composite score of endoscopic severity were associated with a worse probability of eradication, a longer time to eradication and a lower risk of a first recurrence and of bleeding following the procedure, respectively. Ten-year probabilities of overall survival and of bleeding-free survival were 95% and 75%, respectively. CONCLUSIONS: Endoscopic primary prophylaxis of variceal bleeding is reasonably effective and safe in children with high-risk gastroesophageal varices. Worse results are observed in children with more advanced endoscopic features. This pleads for endoscopic screening in children with portal hypertension and early detection of varices warranting primary prophylaxis.

A thermal trade-off between viral production and degradation drives virus-phytoplankton population dynamics.

Marine viruses interact with microbial hosts in dynamic environments shaped by variation in abiotic factors, including temperature. However, the impacts of temperature on viral infection of phytoplankton are not well understood. Here we coupled mathematical modelling with experiments to explore the effect of temperature on virus-phytoplankton interactions. Our model shows the negative consequences of high temperatures on infection and suggests a temperature-dependent threshold between viral production and degradation. Modelling long-term dynamics in environments with different average temperatures revealed the potential for long-term host-virus coexistence, epidemic free or habitat loss states. We generalised our model to variation in global sea surface temperatures corresponding to present and future seas and show that climate change may differentially influence virus-host dynamics depending on the virus-host pair. Temperature-dependent changes in the infectivity of virus particles may lead to shifts in virus-host habitats in warmer oceans, analogous to projected changes in the habitats of macro-, microorganisms and pathogens.

Genetic characterization of B-cell prolymphocytic leukemia: a prognostic model involving MYC and TP53.

B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessments of 34 patients with B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex (≥3 abnormalities) in 73% of the patients and highly complex (≥5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC [t(MYC)] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six (76%) of the 34 patients exhibited an MYC aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1. The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%) and displayed significantly mutated IGHV genes (79%). We identified 3 distinct cytogenetic risk groups: low risk (no MYC aberration), intermediate risk (MYC aberration but no del17p), and high risk (MYC aberration and del17p) (P = .0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We concluded that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease.